The present invention relates to novel N,N-substituted cyclic amine compounds useful as a calcium antagonist, particularly as a nerve-selective calcium antagonist, specifically as an agent for treating and improving the diseases against which an inhibitory action on P/Q type calcium channels or an inhibitory action on N type calcium channels is effective, more specifically as an agent for inhibiting the death of nerve cells or for protecting cerebral nerve cells, and further specifically as an agent for treating and improving nerve diseases, and most specifically as an agent for preventing, treating or improving acute ischemic stroke, cerebral apoplexy, cerebral infarction, head trauma, cerebral nerve cell death, Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, Huntington disease, cerebral circulatory metabolism disturbance, cerebral function disturbance, pain, spasm, schizophrenia, migraine, epilepsy, maniac-depressive psychosis, nerve degenerative diseases, cerebral ischemia, AIDS dementia complications, edema, anxiety disorder (generalized anxiety disorder) and diabetic neuropathy.
In Japan, the number of patients with cerebral apoplexy is about 1.4 million or more per year, and the medical expenses therefor are estimated to be about two billion yen. Cerebral apoplexy is the second cause of death next to malignant tumor and is the biggest cause for bedridden man often suffering from severe secondary diseases. A key to the treatment of cerebral apoplexy is to deal with the acute stage, and the treatment at the acute stage influences the life and function prognosis of the patient and significantly influences secondary diseases.
For the purpose of improving blood stream, several drugs such as ozagrel sodium (thromboxane synthase inhibitor), argatroban (anti-thrombin agent) as an agent for treatment of chronic arterial occlusion, t-PA (alteplase: tissue plasminogen activator which should be used within 3 hours after the onset) as thrombolytic agent etc. are now approved of, or in off lavel use.
In the treatment with these drugs, the following complicated techniques and cautious judgement based on adequate knowledge and experience by a medical specialist are required.
(1) In the case of thrombus-type cerebral infarction, respiratory control, blood pressure control and blood transfusion control are first conducted.
(2) Blood gas and blood pressure are periodically measured.
(3) At the acute stage, reactive high blood pressure is observed, but if complications in the heart and kidney are not observed, treatment for decreasing blood pressure is not conducted.
(4) Then, in the early-acute stage case with no low absorption range observed in CT, the thrombus-lytic agent xe2x80x9curokinasexe2x80x9d is used.
(5) In the case where these agents are not applicable or in the case where 24 hours or more has elapsed after the onset, xe2x80x9cozagrel sodiumxe2x80x9d is administered. Or xe2x80x9cargatrobanxe2x80x9d is administered. However, argatroban is not applicable to lacuna infarction.
(6) To prevent the development of cerebral edema, xe2x80x9cglycerinxe2x80x9d or xe2x80x9cmannitolxe2x80x9d is administered at a suitable dosage.
However, the therapeutic effects of the drugs used heretofore are not satisfactory and further there is the danger that bleeding is often accompanied by their pharmacological effect.
Accordingly, there is the problem that it is difficult for those except of skilled medical specialists to use these drugs.
JP 62-167762-A (EP 229623), JP 2-506694-A (WO 90/13539), DE 4404249, JP 10-95758-A (EP 805147) etc. disclose compounds having piperazine compounds being completely different in structure from the N,N-substituted cyclic amine compounds of the present invention.
The present inventors sought a highly safe drug, which causes no bleeding, and is highly effective in treating and improving the acute ischemic stroke against which no useful drugs have been developed. The inventors focused their attention on nerve-selective, voltage-dependent calcium channel antagonist which directly acts on nerve cells to prevent the development of infarction volume, and they made extensive studies thereon.
As a result, they have found that novel N,N-substituted cyclic amine compounds having the following formula, or pharmacologically acceptable salts thereof, possess an excellent action on inhibition of the death of nerve cells and on protection of cerebral nerve cells, based on inhibitory action on P/Q type calcuim channels or N-type calcium channels. These N,N-substituted cyclic amine compounds are superior in safety and can solve the problems described above, and the present invention has been thereby completed.
The N,N-substituted cyclic amine compounds according to the present invention are represented by the following formula (VIII): 
wherein
A represents an aryl group which may be substituted, a heteroaryl group which may be substituted, an aralkyl group which may be substituted or a heteroaryl alkyl group which may be substituted;
E represents a group represented by the formula xe2x80x94COxe2x80x94 or a group represented by the formula xe2x80x94CHOHxe2x80x94;
G represents an oxygen atom, a sulfur atom, and a group represented by the formula xe2x80x94NR10xe2x80x94 (wherein R10 represents a hydrogen atom, a lower alkyl group, a lower cycloalkyl, a lower acyl group or a lower alkyl sulfonyl group), a group represented by the formula xe2x80x94COxe2x80x94, a group represented by xe2x80x94COOxe2x80x94, a group represented by the formula xe2x80x94OOCxe2x80x94, a group represented by the formula xe2x80x94CONR11xe2x80x94 (wherein R11 represents a hydrogen atom or a lower alkyl group), a group represented by the formula xe2x80x94NR12COxe2x80x94 (wherein R12 represents a hydrogen atom or a lower alkyl group), a group represented by the formula xe2x80x94SOxe2x80x94, a group represented by the formula xe2x80x94SO2xe2x80x94, a group represented by the formula xe2x80x94SONR13xe2x80x94 (wherein R13 represents a hydrogen atom or a lower alkyl group) a group represented by the formula xe2x80x94NR14SOxe2x80x94 (wherein R14 represents a hydrogen atom or a lower alkyl group), a group represented by the formula xe2x80x94SO2NR15xe2x80x94 (wherein R15 represents a hydrogen atom or a lower alkyl group), a group represented by the formula xe2x80x94NR16SO2xe2x80x94 (wherein R16 represents a hydrogen atom or a lower alkyl group), a group represented by the formula  greater than Cxe2x95x90Nxe2x80x94OR17 (wherein R17 represents a hydrogen atom or a lower alkyl group), a group represented by the formula xe2x80x94NHCONHxe2x80x94, a group represented by the formula xe2x80x94NHCSNHxe2x80x94, a group represented by the formula xe2x80x94C(xe2x95x90NH)NHxe2x80x94, a group represented by the formula xe2x80x94NHC(xe2x95x90NH)xe2x80x94, a group represented by the formula xe2x80x94OCOSxe2x80x94, a group represented by the formula xe2x80x94SCOOxe2x80x94, a group represented by the formula xe2x80x94OCOOxe2x80x94, a group represented by the formula xe2x80x94NHCOOxe2x80x94, a group represented by the formula xe2x80x94OCONHxe2x80x94, a group represented by the formula xe2x80x94CO(CH2)sOxe2x80x94, a group represented by the formula xe2x80x94CHOHxe2x80x94 or a group represented by the formula xe2x80x94CHOH(CH2)sOxe2x80x94 (wherein s represents 0 or an integer of 1 to 6);
J represents an aryl group which may be substituted or a heteroaryl group which may be substituted;
R1 represents a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower cycloalkyl group, a hydroxy lower alkyl group, a lower alkoxyalkyl group, a cyano-lower alkyl group, a halogenated lower alkyl group, an optionally N-substituted amino-lower alkyl group, a group represented by the formula xe2x80x94NR18R19 (wherein R18 and R19 may be the same as or different from each other and each represents a hydrogen atom or a lower alkyl group), an aralkyl group, a morpholinyl group, a thiomorpholinyl group, a piperidyl group, a pyrrolidinyl group or a piperazinyl group;
Alk represents a linear or branched lower alkylene group; and
n, v, w, x and y are independent of each other and each represents 0 or 1, and p represents 2 or 3.
The invention includes a pharmacologically acceptable salt of the compound.
Herein, particular examples of the aryl group which may be substituted are phenyl group, naphthyl group etc., or those further substituted with at least one of, for example, a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a hydroxy lower alkyl group, a halogenated lower alkyl group, a hydroxy iminoalkyl group, a cyano group, a nitro group, an optionally N-substituted amino group, an optionally N-substituted carbamoyl group, an optionally N-substituted sulfamoyl group, a lower thioalkoxy group, a lower acyl group, an aromatic acyl group etc.
Particular examples of the heteroaryl group which may be substituted are pyridyl group, pyrazinyl group, pyrimidinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, quinolyl group, isoquinolyl group, quinazolinyl group, phthaladinyl group, quinoxalinyl group, cinnolynyl group, furyl group, thienyl group, thiazolyl gorup etc., or those further substituted.
Particular examples of the aralkyl group which may be substituted are a lower alkyl group substituted with an aryl group, such as benzyl group, phenethyl group, phenylpropyl group, naphthylmethyl group, naphthylethyl group, naphthylpropyl group etc., or that having the aryl group further substituted.
Particular examples of the heteroaryl alkyl group which may be substituted are a lower alkyl group substituted with a heteroaryl group, for example, pyridylmethyl group, pyrazinylmethyl group, pyrimidinylmethyl group, pyrrolylmethyl group, imidazolylmethyl group, pyrazolylmethyl group, quinolylmethyl group, isoquinolylmethyl group, furfuryl group, thienylmethyl group, thiazolylmethyl group etc., or that having the heteroaryl group further substituted.
Particular examples of the halogen atom are fluorine atom, chlorine atom, bromine atom or iodine atom.
Particular examples of the lower alkyl group are linear or branched alkyl groups having 1 to 6 carbon atoms, such as methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, t-butyl group, n-pentyl group, i-pentyl group, t-pentyl group, neopentyl group, hexyl group etc.
Particular examples of the lower alkenyl group are groups derived from linear or branched alkenes having 2 to 6 carbon atoms, such as vinyl group (CH2xe2x95x90CHxe2x80x94), 1-propenyl group (CH3CHxe2x95x90CHxe2x80x94), allyl group (CH2xe2x95x90CHCH2xe2x80x94), isopropenyl (CH2xe2x95x90C(CH3)xe2x80x94) etc.
Particular examples of the lower alkynyl group are groups derived from linear or branched alkynes having 2 to 6 carbon atoms, such as ethynyl group, 1-propynyl group, 2-propynyl group etc.
Particular examples of the lower cycloalkyl group are cyclic alkyl groups having 3 to 8 carbon atoms such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group etc.
Particular examples of the hydroxy lower alkyl group are a group having one or more hydroxy groups bonded to the above-mentioned lower alkyl group, such as a hydroxymethyl group, a hydroxyethyl group, 2,3-dihydroxypropyl group etc.
Particular examples of the cyano-lower alkyl group are a group having one or more cyano groups bonded to the above-mentioned lower alkyl group, such as a cyanomethyl group, a cyanoethyl group, a cyanopropyl group etc.
Particular examples of the halogenated lower alkyl group are a group having one or more halogen atoms, which may be the same as or different from each other, bonded to the above-mentioned lower alkyl group, such as fluoromethyl group, difluoromethyl group, trifluoromethyl group, chloromethyl group, 1-fluoroethyl group, 2-fluoroethyl group, 1,1-difluoroethyl group, 1,2-difluoroethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group etc.
Particular examples of the lower alkoxy group are a group having the above-mentioned lower alkyl group bonded to an oxygen atom, specifically, a linear or branched alkoxy group such as methoxy group, ethoxy group, n-propoxy group, i-propoxy, n-butoxy group, i-butoxy group, t-butoxy group, pentyloxy group, hexyloxy group etc.
Particular examples of the lower acyl group are a linear or branched acyl group derived from fatty acid having 1 to 6 carbon atoms, such as formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group etc.
Particular examples of the amino group which may be substituted are an amino which may be N-substituted by a lower alkyl group, a lower acyl group, a lower alkyl sulfonyl group etc., and the case in which the nitrogen atom is part of a cyclic amine is included. Specifically, an amino group (xe2x80x94NH2), methylamino group (xe2x80x94NHCH3), dimethylamino group (xe2x80x94N(CH3)2), ethylamino group (xe2x80x94NHC2H5), diethylamino group (xe2x80x94N(C2H5)2), methylethylamino group (xe2x80x94N(CH3)C2H5), acetamide group (CH3CONHxe2x80x94), propionamide group (C2H5CONHxe2x80x94), methanesulfonamide group (CH3SO2NHxe2x80x94), ethanesulfonamide group (C2H5SO2NHxe2x80x94), pyrrolidinyl group, pyrazolinyl group, piperidyl group, piperazinyl group, 4-morpholinyl group, 4-thiomorpholinyl group etc. may be proposed.
Particular examples of the carbamoyl group which may be substituted are a carbamoyl group which may be N-substituted by a lower alkyl group etc., and the case in which the nitrogen atom is part of a cyclic amine is included. Specifically, carbamoyl group (xe2x80x94CONH2), N-methylcarbamoyl group (xe2x80x94CONHCH3), N,N-dimethylcarbamoyl group (xe2x80x94CON(CH3)2), N-ethylcarbamoyl group (xe2x80x94CONHC2H5), N,N-diethylcarbamoyl group (xe2x80x94CON(C2H5)2), N-methyl-N-ethylcarbamoyl group (xe2x80x94CON(CH3)C2H5), 1-pyrrolidinylcarbonyl group, 1-pyrazolylcarbonyl group, 1-piperidylcarbonyl group, 1-piperazinylcarbonyl group, 4-morpholinylcarbonyl group, 4-thiomorpholinylcarbonyl group etc. may be proposed.
Particular examples of the sulfamoyl group which may be substituted are a sulfamoyl group which may be N-substituted by a lower alkyl group etc., and the case in which the nitrogen atom is part of a cyclic amine is included. Specifically, sulfamoyl group (xe2x80x94SO2NH2), N-methylsulfamoyl group (xe2x80x94SO2NHCH3), N,N-dimethylsulfamoyl group (xe2x80x94SO2N(CH3)2), N-ethylsulfamoyl group (xe2x80x94SO2NHC2H5), N,N-diethylsulfamoyl group (xe2x80x94SO2N(C2H5)2), N-methyl-N-ethylsulfamoyl group (xe2x80x94SO2N(CH3)C2H5), 1-pyrrolidinylsulfonyl group, 1-pyrazolinylsulfonyl group, 1-piperidylsulfonyl group, 1-piperazinylsulfonyl group, 4-morpholinylsulfonyl group, 4-thiomorpholinylsulfonyl group etc. may be proposed.
Particular examples of the lower thioalkoxy group are a group having the above-mentioned lower alkyl group bonded to a sulfur atom, suchasmethylthiogroup (xe2x80x94SCH3), ethylthio group (xe2x80x94SC2H5) etc.
Particular examples of the lower alkylene group are a divalent group derived from a linear or branched alkane having 1 to 6 carbon atoms, such as methylene group (xe2x80x94CH2xe2x80x94), ethylene group (xe2x80x94CH2CH2xe2x80x94), ethylidene group (xe2x80x94CH(CH3)xe2x80x94), trimethylene group (xe2x80x94CH2CH2CH2xe2x80x94), isopropylidene group (xe2x80x94C(CH3)2xe2x80x94), propylene group (xe2x80x94CH(CH3)CH2xe2x80x94), tetramethylene group (xe2x80x94CH2CH2CH2CH2xe2x80x94), 1,2-butylene group (xe2x80x94CH(C2H5)CH2xe2x80x94), 1,3-butylene group (xe2x80x94CH(CH3)CH2CH2xe2x80x94), 2,3-butylene group (xe2x80x94CH(CH3)CH(CH3)xe2x80x94), isobutylene group (xe2x80x94C(CH3)2CH2xe2x80x94) etc. Moreover, the bonding position (right-handed or left-handed) of the unsymmetrical alkylene group is not limited.
Particular examples of the lower alkoxy carbonyl group are a carbonyl group substituted by the above-mentioned lower alkoxy group, such as methoxy carbonyl group, ethoxy carbonyl group etc.
Particular examples of the lower thioalkoxy group are a group having the above-mentioned lower alkyl group bonded to a sulfur atom, such as methyl thio group, ethyl thio group, propyl thio group etc.
Particular examples of the lower alkyl sulfonyl group are a group having the above-mentioned lower alkyl group bonded to a sulfonyl group, such as methane sulfonyl group, ethane sulfonyl group, propane sulfonyl group etc.
When R20 groups or R21 groups are bonded by themselves to form an alicyclic ring, particular examples of this group are an alicyclic condensed phenyl group such as indanyl group, tetralinyl group etc., or a group in which the alicyclic group or phenyl group is further substituted.
When R20 groups or R21 groups are bonded by themselves to form a hetero ring, particular examples of this ring are a hetero ring condensed with phenyl group, such as benzofuranyl group, chromanyl group, isochromanyl group, indolynyl group, isoindolynyl group, teterhydroquinolyl group, tetrahydroisoquinolyl group, or groups in which the hetero ring or phenyl group is further substituted.
When R20 groups or R21 groups are bonded by themselves to form an alkylene dioxy group, particular examples of this group are methylene dioxy phenyl group, ethylene dioxy phenyl group, or groups in which the phenyl group is further substituted.
Herein, particular examples of the aryl group which may be substituted are phenyl group, naphthyl group etc., or groups having these groups further substituted.
Particular examples of the heteroaryl group which may be substituted are pyridyl group, pyrazinyl group, pyrimidinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, quinolyl group, isoquinolyl group, quinazolinyl group, phthaladinyl group, quinoxalinyl group, cinnolynyl group, furyl group, thienyl group, thiazolyl group etc., or groups having these groups further substituted.
Particular examples of the aralkyl group which may be substituted are a lower alkyl group substituted with an aryl group, such as benzyl group, phenethyl group, phenyl propyl group, naphthyl methyl group, naphthyl ethyl group, naphthyl propyl group etc., or groups having the aryl group further substituted.
Particular examples of the heteroaryl alkyl group which may be substituted are a lower alkyl group substituted with a heteroaryl group, for example, pyridyl methyl group, pyrazinyl methyl group, pyrimidinyl methyl group, pyrrolyl methyl group, imidazolyl methyl group, pyrazolyl methyl group, quinolyl methyl group, isoquinolyl methyl group, furfuryl group, thienyl methyl group, thiazolyl methyl group etc., or groups having the heteroaryl group further substituted.
Particular examples of the lower alkyl group are C1 to C6 alkyl groups, such as methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, t-butyl group, pentyl group, hexyl group etc.
Particular examples of the lower cycloalkyl group are C3 to C8 cycloalkyl groups, such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cycloctyl group etc.
Herein, particular examples of the halogen atom are fluorine atom, chlorine atom, bromine atom or iodine atom.
Particular examples of the lower alkoxy group are a group having the above-mentioned lower alkyl group bonded to an oxygen atom, such as methoxy group, ethoxy group, propoxy group etc.
Particular examples of the amino group which may be substituted are an amino group or a group wherein 1 or 2 hydrogen atoms in the amino group is substituted by lower alkyl group etc., such as methyl amino group, ethyl amino group, dimethyl amino group, diethyl amino group, methyl ethyl amino group etc.
Particular examples of the lower alkoxy carbonyl group are a carbonyl group substituted by the above-mentioned lower alkoxy group, such as methoxy carbonyl group, ethoxy carbonyl group etc.
Particular examples of the lower thioalkoxy group are a group having the above-mentioned lower alkyl group bonded to a sulfur atom, such as methyl thio group, ethyl thio group, propyl thio group etc.
Particular examples of the lower alkyl sulfonyl group are a group having the above-mentioned lower alkyl group bonded to a sulfonyl group, such as methane sulfonyl group, ethane sulfonyl group, propane sulfonyl group etc.
Particular examples of the lower acyl group are a group having the above-mentioned lower alkyl group bonded to a carbonyl group, such as acetyl group, propionyl group, butyroyl group etc.
When R20 groups or R21 groups are bonded to form an alicyclic ring, particular examples of this group are an alicyclic condensed phenyl group such as indanyl group, tetralinyl group etc., or the group in which alicyclic group or phenyl group is further substituted.
When R20 groups or R21 groups are bonded to form a hetero ring, particular examples of this ring are a hetero ring condensed with phenyl group, such as benzofuranyl group, chromanyl group, isochromanyl group, indolynyl group, isoindolynyl group, teterhydroquinolyl group, tetrahydroisoquinolyl group, or groups in which the hetero ring or phenyl group is further substituted.
When R20 groups or R21 groups are bonded to form an alkylene dioxy group, particular examples of this group are methylene dioxy phenyl group, ethylene dioxy phenyl group, or groups in which the phenyl group is further substituted.
The invention includes as an embodiment an N,N-substituted cyclic amine compound (I) represented by the following formula (I): 
wherein
A represents an aryl group which may be substituted, a heteroaryl group which may be substituted, an aralkyl group which may be substituted or a heteroaryl alkyl group which may be substituted;
E represents a group represented by the formula xe2x80x94COxe2x80x94 or a group represented by the formula xe2x80x94CHOHxe2x80x94;
G represents an oxygen atom, a sulfur atom, and a group represented by the formula xe2x80x94NR10xe2x80x94 (wherein R10 represents a hydrogen atom, a lower alkyl group, a lower acyl group or a lower alkyl sulfonyl group), a group represented by the formula xe2x80x94COxe2x80x94, a group represented by xe2x80x94COOxe2x80x94, a group represented by the formula xe2x80x94OOCxe2x80x94, a group represented by the formula xe2x80x94CONR11xe2x80x94 (wherein R11 represents a hydrogen atom or a lower alkyl group) a group represented by the formula xe2x80x94NR12COxe2x80x94 (wherein R12 represents a hydrogen atom or a lower alkyl group), a group represented by the formula xe2x80x94SOxe2x80x94, a group represented by the formula xe2x80x94SO2xe2x80x94, a group represented by the formula xe2x80x94SONR13xe2x80x94 (wherein R13 represents a hydrogen atom or a lower alkyl group) a group represented by the formula xe2x80x94NR14SOxe2x80x94 (wherein R14 represents a hydrogen atom or a lower alkyl group), a group represented by the formula xe2x80x94SO2NR15xe2x80x94 (wherein R15 represents a hydrogen atom or a lower alkyl group), a group represented by the formula xe2x80x94NR16SO2xe2x80x94 (wherein R16 represents a hydrogen atom or a lower alkyl group), a group represented by the formula  greater than Cxe2x95x90Nxe2x80x94OR17 (wherein R17 represents ahydrogen atom or a lower alkyl group), a group represented by the formula xe2x80x94NHCONHxe2x80x94, a group represented by the formula xe2x80x94NHCSNHxe2x80x94, a group represented by the formula xe2x80x94C(xe2x95x90NH)NHxe2x80x94, a group represented by the formula xe2x80x94NHC (xe2x95x90NH)xe2x80x94, a group represented by the formula xe2x80x94OCOSxe2x80x94, a group represented by the formula xe2x80x94SCOOxe2x80x94, a group represented by the formula xe2x80x94OCOOxe2x80x94, a group represented by the formula xe2x80x94NHCOOxe2x80x94, a group represented by the formula xe2x80x94OCONHxe2x80x94, a group represented by the formula xe2x80x94CO(CH2)sOxe2x80x94, a group represented by the formula xe2x80x94CHOHxe2x80x94 or a group represented by the formula xe2x80x94CHOH(CH2)sOxe2x80x94 (wherein s is 0 or an integer of 1 to 6);
J represents an aryl group which may be substituted or a heteroaryl group which may be substituted;
R1 represents a lower alkyl group, a lower cycloalkyl group, a group represented by the formula xe2x80x94NR18R19 (wherein R18 and R19 may be the same or different from each other and each represents a hydrogen atom or a lower alkyl group), a morpholinyl group, a thiomorpholinyl group, a piperidyl group, a pyrrolidnyl group or a piperazinyl group;
R2, R3, R4, R5, R6, R7, R8 and R9 may be the same or different from each other and each represents a hydrogen atom or a lower alkyl group; and
m, o, q, and r may be the same or different from each other and each represents 0 or an integer of 1 to 6, n is 0 or 1, and p is 2 or 3.
Next, the invention includes as an embodiment an N,N-substituted cyclic amine compound (II) represented by the following formula (II): 
wherein A, E, G, J, R1, m, n, o, p, q and r have the same meanings as defined above.
Next, the invention includes as an embodiment an N,N-substituted cyclic amine compound (III) represented by the following formula (III): 
wherein A, G, J, R1, m, p and q have the same meanings as defined above.
Finally, the invention includes as an embodiment an N,N-substituted cyclic amine compound (IV) represented by the following formula (IV): 
wherein
R1, m, p, and q have the same meanings as defined above;
R20 and R12 are the same or different from each other and each represents a hydrogen atom, a halogen atom, a hydroxy group, a mercapto group, a lower alkyl group, a lower alkoxy group, a hydroxymethyl group, a nitro group, an amino group which may be substituted, a cyano group, a carboxyl group, a lower alkoxy carbonyl group, a lower thioalkoxy group, a lower alkyl sulfonyl group, a lower acyl group, a halogenated lower alkyl group, an aryl group which may be substituted, a heteroaryl group which may be substituted, an aryloxy group, an aralkyloxy group, a lower alkoxycarbonylalkoxy group or a hydroxy lower alkoxy group, and R20 groups or R21 groups may form an alicyclic group which may be substituted, or a heterocyclic group or alkylene dioxy group which may be substituted; and
j and t may be the same or different from each other and each represents 0 or an integer of 1 to 5.
The N,N-substituted cyclic amine compounds (VIII) and those having formulas (I) to (IV) according to the present invention contain 1 or more asymmetric carbon atoms in the molecule, so their optical isomers or meso forms can exist, but the present invention is not limited. The present invention encompasses any of the optical isomers, meso forms and racemates of these compounds. Further, these include not only anhydrides but also hydrates and polymorphs.
When producing the optically active substances, optically active starting materials can be used for asymmetric synthesis, or racemates can be optically resoluted by column chromatography or crystallization.
The pharmacologically acceptable salts in the present invention are not limited insofar as they form salts with the N,N-substituted cyclic amine compounds (VIII) and (I) to (IV) of the present invention, and particular examples are inorganic acid addition salts such as hydrochloride, sulfate, nitrate, hydrobromate, hydriodate, perchlorate, phosphate etc., organic acid addition salts such as oxalate, maleate, fumarate, succinate etc., sulfonic acid addition salts such as methane sulfonate, ethane sulfonate, benzene sulfonate, p-toluene sulfonate, camphor sulfonate, and amino acid addition salts, among which hydrochloride and oxalate are preferable.
More specific examples of the N,N-substituted amine compounds (VIII) and (I) to (IV) according to the present invention include the following compounds which are not intended to limit the present invention:
(1) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(2) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[3-(4-fluorophenoxy)propyl]piperazine
(3) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]homopiperazine
(4) 1-[(3-cyano-4-methyl-3-phenyl)pentyl]-4-[2-(4-fluorophenoxy)ethyl]homopiperazine
(5) 1-[(3-cyano-4-methyl-3-phenyl)pentyl]-4-[3-(4-fluorophenoxy)propyl]piperazine
(6) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-(4-phenoxybutyl)piperazine
(7) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-phenoxyethyl]piperazine
(8) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-nitrophenoxy)ethyl]piperazine
(9) 1-[4-cyano-5-methyl-4-(4-methylphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(10) 1-[4-cyano-5-methyl-4-(4-chlorophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(11) 1-[4-cyano-5-methyl-4-(4-methoxyphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(12) 1-[4-cyano-5-methyl-4-(4-carbomethoxyphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(13) 1-[4-cyano-5-methyl-4-(4-hydroxymethylphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(14) 1-[4-cyano-5-methyl-4-(4-hydroxyiminomethylphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(15) 1-[4-cyano-5-methyl-4-(4-cyanophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(16) 1-[4-cyano-5-methyl-4-(4-nitrophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(17) 1-[4-cyano-5-methyl-4-(4-aminophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(18) 1-[4-cyano-5-methyl-4-(4-acetamidophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(19) 1-[4-cyano-5-methyl-4-(4-dimethylaminophenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(20) 1-{[4-cyano-5-methyl-4-(2-thienyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine
(21) 1-{[4-cyano-5-methyl-4-(3-pyridyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine
(22) 1-{[4-cyano-5-methyl-4-(2-fluorophenyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine
(23) 1-{[4-cyano-5-methyl-4-(3-fluorophenyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine
(24) 1-{[4-cyano-5-methyl-4-(4-fluorophenyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine
(25) 1-[(3-cyano-4-methyl-3-phenyl)pentyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(26) 1-[(4-cyano-4-phenyl)pentyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(27) 1-[(4-cyano-4-phenyl)heptyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(28) 1-[(4-cyano-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(29) 1-[(4-cyano-4-phenyl)octyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(30) 1-[(4-cyano-6-methyl-4-phenyl)heptyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(31) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-fluorophenoxy)ethyl]piperazine
(32) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-fluorophenoxy)ethyl]piperazine
(33) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[3-(4-fluorophenoxy)pentyl]piperazine
(34) 1-[(4-cyano-5-methyl-4-phenyl)heptyl]-4-[3-(4-fluorophenoxy)ethyl]piperazine
(35) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3,4-difluorophenoxy)ethyl]piperazine
(36) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-chlorophenoxy)ethyl]piperazine
(37) 1-{[4-cyano-5-methyl-4-(3,4-dichlorophenyl)hexyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine
(38) 1-[(4-cyano-4-cyclohexyl-4-phenyl)butyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(39) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-methoxyphenoxy)ethyl]piperazine
(40) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2,3-dimethoxyphenoxy)ethyl]piperazine
(41) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3,4-dimethoxyphenoxy)ethyl]piperazine
(42) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-aminophenoxy)ethyl]piperazine
(43) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-dimethylaminophenoxy)ethyl]piperazine
(44) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-acetamidophenoxy)ethyl]piperazine
(45) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-methylthiophenoxy)ethyl]piperazine
(46) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-cyanophenoxy)ethyl]piperazine
(47) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-cyanophenoxy)ethyl]piperazine
(48) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(benzyloxy)ethyl]piperazine
(49) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenylthio)ethyl]piperazine
(50) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenylsulfonyl)ethyl]piperazine
(51) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenylamino)ethyl]piperazine
(52) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-fluorophenyl)-N-methylamino]ethyl}piperazine
(53) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-fluorophenyl)-N-acetylamino]ethyl}piperazine
(54) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-fluorophenyl)-N-methanesulfonylamino]ethyl}piperazine
(55) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(benzylamino)ethyl]piperazine
(56) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-acetyl-N-benzylamino)ethyl]piperazine
(57) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-methanesulfonyl-N-benzylamino)ethyl]piperazine
(58) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-benzyl-N-isopropylamino)ethyl]piperazine
(59) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorobenzoyl)ethyl]piperazine
(60) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[3-hydroxy-3-(4-fluorophenyl)propyl]piperazine
(61) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)acetyl]piperazine
(62) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-hydroxy-3-(4-fluorophenoxy)propyl]piperazine
(63) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenylaminocarbonyl)ethyl]piperazine
(64) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorobenzoylamino)ethyl]piperazine
(65) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[N-(4-fluorophenyl)carbamoylmethyl]piperazine
(66) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorobenzenesulfonylamino)ethyl]piperazine
(67) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-fluorophenyl)sulfamoyl]ethyl}piperazine
(68) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-(4-fluorophenyl)-N-methylsulfamoyl]ethyl}piperazine
(69) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-methyl-4-fluorobenzenesulfonylamino)ethyl]piperazine
(70) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[(4-fluorophenylthio)carbonyloxy]ethyl}piperazine
(71) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-pyridyloxy)ethyl]piperazine
(72) 1-(3-cyclohexyl-3-cyano-3-phenyl)propionyl-4-[2-(4-fluorophenoxy)ethyl]piperazine
(73) 1-(2-hydroxy-4-cyano-5-methyl-4-phenyl)hexyl-4-[2-(4-fluorophenoxy)ethyl]piperazine
(74) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-benzylphenoxy)ethyl]piperazine
(75) 1-[(4-cyano-5-hydroxy-5-methyl-4-phenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(76) 1-[5-(4-cyano-5-methyl-4-phenyl)hexenyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(77) 1-[4-cyano-5-methyl-4-(4-hydroxyphenyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(78) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-hydroxy-4-fluorophenoxy)ethyl]piperazine
(79) 1-[(4-cyano-4-fluoro-4-phenyl)butyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(80) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-ethoxycarbonylmethoxy-4-fluorophenoxy)ethyl]piperazine
(81) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-hydroxyethoxy-4-fluorophenoxy)ethyl]piperazine
(82) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-methoxy-4-fluorophenoxy)ethyl]piperazine
(83) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-isopropylanilino)ethyl]piperazine
(84) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(N-cyclohexylanilino)ethyl]piperazine
(85) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl(4-isopropylanilino)ethyl]}piperazine
(86) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl(3-isopropylanilino)ethyl]}piperazine
(87) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[N-methyl(2-isopropylanilino)ethyl]}piperazine
(88) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3,4-(methylenedioxy)phenoxy]ethyl}piperazine
(89) Synthesis of 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(6-quinolyloxy)ethyl]piperazine
(90) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(5-isoquinolyloxy)ethyl]piperazine
(91) 1-[{2-(5-cyano-6-methyl-5-phenyl)heptyl}]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(92) 1-{[4-(7-cyano-8-methyl-7-phenyl)nonyl]}-4-[2-(4-fluorophenoxy)ethyl]piperazine
(93) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-pyridyloxy)ethyl]piperazine
(94) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-pyridyloxy)ethyl]piperazine
(95) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(5-quinolyloxy)ethyl]piperazine
(96) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-trifluoromethylphenoxy)ethyl]piperazine
(97) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(1-naphthyloxy)ethyl]piperazine
(98) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-ethyl-2-(4-fluorophenoxy)ethyl]piperazine
(99) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-quinazolinyloxy)ethyl]piperazine
(100) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[4-(3-pyridyl)phenoxy]ethyl}piperazine
(101) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3-(3-pyridyl)phenoxy]ethyl}piperazine
(102) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(4-bromophenoxy)ethyl]piperazine
(103) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-bromophenoxy)ethyl]piperazine
(104) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-bromophenoxy)ethyl]piperazine
(105) 1-[(4-Cyano-5-methyl-4-phenyl)hexyl]-4-{2-[4-(imidazol-1-yl)phenoxy]ethyl}piperazine
(106) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(2-pyrimidinyloxy)ethyl]piperazine
(107) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[2-(3-pyridyl)phenoxy]ethyl}piperazine
(108) 1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine
(109) 1-[4-cyano-5-methyl-4-(2-cyano-5-thienyl)hexyl]-4-[2-(3-fluorophenoxy)ethyl]piperazine
(110) 1-[4-cyano-5-methyl-4-(2-thienyl)hexyl]-4-[2-(3-fluorophenoxy)ethyl]piperazine
(111) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3-(3-thienyl)phenoxy]ethyl}piperazine
(112) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[2-(6-methyl-2-pyridyl)vinylphenoxy]ethyl}piperazine
(113) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-cyanophenoxy)ethyl]piperazine
(114) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-[2-(3-phenylphenoxy)ethyl]piperazine
(115) 1-[(4-cyano-5-methyl-4-phenyl)hexyl]-4-{2-[3-(2-cyanovinyl)phenoxy]ethyl}piperazine
(116) 1-[(4-cyano-5-methyl-4-phenyl)hexanoyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine and
(117) 1-[(4-cyano-4-phenyl)butyl]-4-[2-(4-fluorophenoxy)ethyl]piperazine.
The compounds of the present invention have extremely high LD50 and extremely high safety.
Among the above compounds of the present invention, for example, compounds of (1), (9), (10), (11), (20), (22), (23), (24), (36), (52), (75), (76), (79), (86), (88), (92), (95), (104), (107), (109) and (116) are preferable from the viewpoin of a pharmacological activity and safety.
Next, the process for producing the N,N-substituted cyclic amine compounds according to the present invention is not limited, and for example it can be produced in the following manner.
In this case, aldehyde compound (IX) and cyclic amine (X) can be reacted in the presence of a reducing agent according to conventional reductive amination, for example a method described in shin Jikken Kagaku Koza 14-III, page 1373, published by Maruzen K. K. This reaction is shown in the following chemical scheme: 
wherein A, E, G, J, Alk, R1, v, n, w, x, y and p have the same meanings as defined above.
Here in, the reducing agent is not limited insofar as it is conventionally used for reductive N-alkylation, and preferable examples include sodium triacetoxy borohydride, sodium cyano borohydride, sodium borohydride, lithium aluminum hydride etc.
In a method other than (1), the desired compound can be synthesized by adding active alkyl compound (XII) to cyclic amine (XI) in the presence of a base. This reaction is shown in the following reaction scheme: 
wherein A, E, G, J, Alk, R1, v, n, w, x, y and p have the same meanings as defined above. L is a leaving group such as halogen atom, methane sulfonyloxy group etc.
In this case, aldehyde compound (V) and cyclic amine (VI) can be reacted in the presence of a reducing agent according to conventional reductive amination, for example a method described in Shin Jikken Kagaku Koza 14-III, page 1373, published by Maruzen K. K. This reaction is shown in the following chemical scheme: 
wherein A, E, G, J, R1, R2, R3, R4, R5, R6, R7, R8, R9, m, n, o, p, q and r have the same meanings as defined above.
Herein, the reducing agent is not limited insofar as it is conventionally used for reductive N-alkylation, and preferable examples include sodium triacetoxy borohydride, sodium cyano borohydride, sodium borohydride, lithium aluminum hydride etc.
In a method other than (3), the desired compound can be synthesized by adding active alkyl compound (VII) to cyclic amine (VI) in the presence of a base. This reaction is shown in the following reaction scheme: 
wherein A, E, G, J, R1, R2, R3, R4, R5, R6, R7, R8, R9, m, n, o, p, q, and r have the same meanings as defined above. L is a leaving group such as halogen atom, methane sulfonyloxy group etc.
The administration form of the compounds of the present invention include e.g. oral pharmaceutical preparations such as powder, fine granule, granule, tablet, coated tablet and capsule, external application such as ointments, plaster and suppository, as well as injection. For pharmaceutical composition manufacturing, conventional pharmaceutical carriers can be used in a usual manner.
That is, for production of oral pharmaceutical composition, N,N-substituted cyclic amine compounds or pharmacologically acceptable salts thereof and fillers, and as necessary binders, disintegrators, lubricants, coloring agents, taste and odor correctives etc. mixed and formed in a usual manner to form powder, fine granule, granule, tablet, coated tablet, capsule etc.
The fillers include e.g. milk sugar, corn starch, white sugar, glucose, mannitol, sorbit, crystalline cellulose, silicon dioxide etc.; the binders include e.g. polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polypropylene glycol-polyoxyethylene block polymers, meglumine etc.; the disintegrators include e.g. starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, carboxymethyl cellulose calcium etc.; the lubricants include e.g. magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oil; the coloring agents include those approved to be added to pharmaceutical composition; and the taste and odor correctives include cocoa powder, menthol, aromatic powder, peppermint oil, camphor, cinnamon powder. These tablets and granules may be coated with sugar-coatings or any other materials as necessary.
For production of pharmaceutical composition for injection, pH adjustors, dissolution agents, isotonicity-imparting agents etc. and as necessary dissolution assistants, stabilizers etc. are added to the N,N-substituted cyclic amine compounds or pharmacologically acceptable salts thereof, to manufacture pharmaceutical composition in a usual manner.
The method of producing the pharmaceutical composition for external application is not limited, and these can be produced in a usual manner. That is, the base starting materials used in pharmaceutical manufacturing may be various starting materials conventionally used in pharmaceutical compositions, non-pharmaceutical compositions, cosmetics etc.
Specifically, the base starting materials include e.g. raw materials such as animal and vegetable oil, mineral oil, ester oil, waxes, higher alcohols, fatty acids, silicon oil, surfactants, phospholipids, alcohols, polyols, water-soluble polymers, clays and minerals, purified water etc., and as necessary, pH adjustors, antioxidants, chelating agents, preservatives, anti-fungus agents, coloring agents, perfumes etc., but the base starting materials for external application according to the present invention are not limited to those enumerated above. Further, components having differentiation-inducing action, blood stream promoters, disinfectants, anti-inflammatory agents, cell activators, vitamins, amino acids, humectants, keratin-lytic agent etc. can also be incorporated. The amount of these base starting materials is usually determined as an amount used in producing preparations for external application.
In the present invention, the clinical dosage of the N,N-substituted cyclic amine compounds or pharmacologically acceptable salts thereof is not limited, and the dosage varies depending on conditions, severity, age, complications etc. and on the type of salt and administration route. This dosage is in the range of usually 0.01 to 1000 mg, preferably 0.1 to 500 mg, and more preferably 0.5 to 100 mg per day for an adult, and it is administered orally, intravenously, as suppository or percutaneously.
Hereinafter, the excellent pharmacological effects of the compounds of the present invention are mentioned as the effects of the invention.
For example, the following literatures describe that compounds having an inhibitory action on N type or P/Q type calcium channels can serve as an agent for inhibiting the death of nerve cells or for protecting cerebral nerve cells, an agent for treating or improving nervous diseases, an agent for treating or improving acute ischemic stroke, head trauma, death of nerve cells, Alzheimer disease, cerebral circulatory metabolism disturbance, cerebral function disturbance or pain, an anti-spasm agent, an agent for treating or improving schizophrenia and an agent for preventing, treating or improving migraine, epilepsy, maniac-depressive psychosis, nerve degenerative diseases (Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease) cerebral ischemia, epilepsy, head trauma, AIDS dementia complications, edema, anxiety disorder (generalized anxiety disorder) and diabetic neuropathy.
(1) Acute ischemia stroke: Annj. Rev. Physiol., 52, 543-559, 1990.
(2) Head trauma: SCRIP, No. 2203, 24, 1997.
(3) Ischemiaxe2x80x94death of cerebral nerve cells: Advances in Pharmacology, 22, 271-297, 1991.
(4) Alzheimer disease: Trends in Neuroscience, 16, 409, 1993.
(5) Cerebral circulatory metabolism disturbance: Nichiyakurishi, 85, 323-328, 1985.
(6) Cerebral function disturbance: Acta Neurol. Scand., 78:2, 14-200, 1998.
(7) Analgesic: Drug of the Future, 23 (2), 152-160, 1998.
(8) Cerebral ischemia, migraine, epilepsy, maniac-depressive psychosis: CasopisLekau Ceskych., 130 (22-23), 625-630, 1991.
(9) Nerve degenerative diseases (Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease), cerebral ischemia, epilepsy, head trauma, and AIDS dementia complications: Revista de Neurologia., 24 (134), 1199-1209, 1996.
Further, for example, the following literatures describe that compounds having an inhibitory action on N type or P/Q type calcium channels can serve as an agent for preventing, treating or improving edema, anxiety disorder (generalized anxiety disorder), schizophrenia, diabetic neuropathy and migraine.
(10) Edema: Brain Research, 776, 140-145, 1997.
(11) Anxiety disorder (generalized anxiety disorder), schizophrenia: Jyunkanseigyo (Circulation Control), 14 (2), 139-145, 1993.
(12) Diabetic neuropathy: Shinkeinaika (Neurological Medicine), 50, 423-428, 1999.
(13) Migraine: Neurology, 50 (4), 1105-1110, 1998.
Accordingly the invention provides a calcium antagonist comprising the N,N-substituted cyclic amine compounds or a pharmacologically acceptable salt thereof; a nerve-selective calcium antagonist comprising the N,N-substituted cyclic amine compounds or a pharmacologically acceptable salt thereof; an agent for preventing, treating and improving the diseases against which an inhibitory action on P/Q type calcium channel is effective, comprising the N,N-substituted cyclic amine compounds or a pharmacologically acceptable salt thereof; an agent for preventing, treating and improving the diseases against which an inhibitory action on N type calcium channel is effective, comprising the N,N-substituted cyclic amine compounds or a pharmacologically acceptable salt thereof; an agent for inhibiting the death of nerve cells or for protecting brain nerve cells, comprising the N,N-substituted cyclic amine compounds or a pharmacologically acceptable salt thereof; an agent for preventing, treating or improving a nerve disease, comprising the N,N-substituted cyclic amine compounds or a pharmacologically acceptable salt thereof wherein the nerve cell disease may be one disease selected from the group consisting of acute ischemic stroke, cerebral apoplexy, cerebral infarction, head trauma, cerebral nerve cell death, Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, Huntington disease, cerebral circulatory metabolism disturbance, cerebral function disturbance, pain, spasm, schizophrenia, migraine, epilepsy, maniac-depressive psychosis, nerve degenerative diseases, cerebral ischemia, AIDS dementia complications, edema, anxiety disorder (generalized anxiety disorder) and diabetic neuropathy; and a calcium antagonist composition comprising a pharmacologically effective amount of the N,N-substituted cyclic amine compounds or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier.
Moreover the present invention provides a method of treating a disease against which calcium antagonism is effective, which comprises administering a pharmacologically effective amount of the N,N-substituted cyclic amine compounds or a pharmacologically acceptable salt thereof to a patient suffering from the disease; and use of the N,N-substituted cyclic amine compounds or a pharmacologically acceptable salt thereof for manufacturing calcium antagonist.